New Treatment Shows 80% Response Rate in a Phase I Clinical Trial, Becomes a “Breakthrough Therapy”

Cancer is a complex disease to diagnose and treat. Cancer care plans are based not only on the disease type and how advanced it is, but some treatments can now target a patient’s specific genetic variations that may be driving cancer growth. Targeted therapies can act as inhibitors to a cancer-fueling mutated gene—essentially applying the brakes to a floored gas pedal.

Such is the case with non-small cell lung cancers (NSCLC) that have the anaplastic lymphoma kinase (ALK) gene mutation. The targeted therapy currently used with this diagnosis, crizotinib, acts as an inhibitor of the ALK gene mutation known to drive NSCLC growth. Some of these cases respond to crizotinib; however, some cases show no response and some develop a resistance to it.

What Are Phase I Clinical Trials?

Phase I trials are first-time tests of drugs or treatments on human patients. At this stage, researchers do not know the drug’s effectiveness, the best dose to give, or what side effects may occur, but they believe it to be beneficial. A suggested starting dose for humans is found through lab experiments. All patients involved in phase I clinical trials receive a form of treatment; none are administered placebos (inactive agents sometimes used for comparison purposes).

In his leadership role with the Center for Investigational Therapeutics, Sharma aims to facilitate the collaboration between lab research and physicians, resulting in phase I studies.

“Phase I clinical trials truly are critical in oncology,” says Sharma, referring to a recent statement from the American Society of Clinical Oncology urging participation in phase I trials. “Five to ten years ago, you couldn’t go from a phase I trial to clinical application. This is a new world we’re living in, and it’s very exciting.”

NSCLC is the most common type of lung cancer, accounting for 85-90% of all cases. Approximately 3-8% of patients with it have the ALK gene mutation. There are limited treatment options for these patients, who tend to be non-smokers and younger than NSCLC patients without the ALK gene mutation.

A new investigational ALK inhibitor, ceritinib, studied at Huntsman Cancer Institute (HCI) as part of a worldwide phase I clinical trial, has shown greater cancer-fighting potential than crizotinib in preclinical studies. In fact, based on the successful results of this phase I trial, the U.S. Food and Drug Administration (FDA) granted accelerated approval to ceritinib in April 2014.

“This opens a new avenue of targeted therapies and lays groundwork for future research,” says Sunil Sharma, MBA, MD, Senior Director of Clinical Research and Director of the Center for Investigational Therapeutics at HCI, and professor in the Department of Internal Medicine at the University Of Utah School of Medicine.

Initial results of this phase I study were reported in the March 2014 New England Journal of Medicine. The study looked at the maximum tolerated dose, safety, pharmacokinetics, and antitumor activity of ceritinib in 88 patients who had advanced NSCLC with the ALK gene mutation and were intolerant to crizotinib or whose cancer had progressed during treatment with it. The data showed a response rate of 80% in patients whose disease progressed after crizotinib treatment. Sharma says additional opportunities for research come from this study.

“This allows us a look into what made some patients resistant to crizotinib and to test new combinations of therapies tailored to each patient,” says Sharma. “Focusing on molecular and genomic annotation to develop targeted therapies, we can then predict which patients will benefit from which therapeutic approaches.”

This umbrella of medical care, called precision medicine, targets therapies to an individual’s genetic abnormalities that cause disease. Ceritinib shows such promise in this area that it received a Breakthrough Therapy designation in 2013 by the FDA. According to the FDA, this designation expedites the process to develop and review drugs that treat serious or life-threatening conditions if the therapy shows substantial improvement over current treatment. The designation includes all of the fast-track program features, as well as more intensive FDA guidance.

Ceritinib is still an investigational therapy, meaning further clinical trials will help researchers better understand the full scope of its potential benefits and risks. Sharma stresses the importance of clinical trials to discover new treatments such as ceritinib—a process that begins with phase I trials. “First and foremost, it is really about the patients. It gives them hope knowing they are getting the most cutting-edge treatments available. We ultimately will be able to pair patients with the most effective therapeutic approach matched to their genetic structure.”

President’s Precision Medicine Initiative

In January 2015, President Barack Obama announced the Precision Medicine Initiative. This new research effort will pioneer a new model of patient-powered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients. Sharma’s phase I trial for ceritinib showing such success, with the subsequent Breakthrough Therapy designation by the FDA, is the ideal example of this initiative in action.

Most medical treatments have been designed for the average patient. As a result of this one-size-fits-all approach, treatments can be very successful for some patients but not for others. This is changing with the emergence of precision medicine, the approach to disease prevention and treatment that takes into account individual differences in people’s genes, environments, and lifestyles. Precision medicine gives clinicians tools to better understand the complex mechanisms underlying a patient’s health, disease, or condition, and to better predict which treatments will be most effective.

Advances in precision medicine have already led to powerful new discoveries and several new treatments tailored to specific characteristics of individuals, such as a person’s genetic makeup, or the genetic profile of an individual’s tumor. This is leading to a transformation in the way we can treat diseases such as cancer. Patients with breast, lung, and colorectal cancers, as well as melanomas and leukemias, for instance, routinely undergo molecular testing as part of patient care, enabling physicians to select treatments that improve chances of survival and reduce exposure to adverse effects. Read a White House factsheet about this initiative or view a PDF of the Precision Medicine Infographic from the National Institutes of Health.